The success or failure of a pregnancy is largely determined during the first weeks of pregnancy. In the course of these events the placentation site is constructed and the level of communication between mother and fetus established. Fundamental to this process is the restructuring of uterine spiral arteries. These blood vessels are the conduit that delivers nutrients to the developing placenta and fetus. Two key cell types are pivotal to reshaping and redirecting the function of the uterine spiral arteries: natural kille (NK) cells and invasive extravillous trophoblast cells. NK cells are an integral component of the maternal innate immune system and are recruited and expanded at the site of intrauterine embryo implantation. Invasive extravillous trophoblast cells represent a specialized lineage of trophoblast cells targeted to the endometrium, especially the endometrial arterial vasculature. The activities of NK cells and invasive trophoblast are precisely orchestrated, both temporally and spatially, to guide establishment of the maternal-fetal interface. Disruptions in the coordination of these events results in severe consequences to mother, fetus, newborn, and future adult; as observed in the pregnancy disease, preeclampsia. The rat exhibits deep trophoblast invasion and extensive NK cell-directed and trophoblast-directed uterine spiral artery remodeling; and represents an exquisite animal model for gaining mechanistic insights into the establishment of pregnancy, including events transpiring during human hemochorial placentation. NK cells direct the first wave of pregnancy-dependent uterine spiral artery remodeling. These NK cell-guided vascular changes are measured and precede trophoblast-directed uterine spiral artery remodeling. After midgestation NK cells disappear and invasive extravillous trophoblast cells expand and represent the primary engineers of uterine vascular remodeling. In the absence of NK cells (via immunodepletion), invasion of extravillous trophoblast and uterine spiral artery remodeling are precocious and extensive. We therefore view NK cells as directors of an essential maternal protective response to pregnancy. Depletion of NK cells impairs uterine spiral artery development leading to hypoxia at the placentation site, which results in the redirection of trophoblast differentiation to the invasive extravillous trophoblast lineage. Thus it is apparent that there is a dynamic interplay between NK cells and invasive extravillous trophoblast during hemochorial placentation. We predict that disruptions in the activities of this maternal cell population (NK cells) and this extraembryonic cell population (invasive extravillous trophoblast cells) will have consequences on the success of pregnancy. In this proposal we explore the role of NK cells in hemochorial placentation and pregnancy-related diseases.